Impact of Lipid-Lowering Therapy on Pancreatic Health: Insights from Mendelian Randomization

Impact of Lipid-Lowering Therapy on Pancreatic Health: Insights from Mendelian Randomization | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Impact of Lipid-Lowering Therapy on Pancreatic Health: Insights from Mendelian Randomization Ge Yang, Yizhuo Feng, Yanjiao Ou, Hong Zhang, Can-E Tang, Yongchuan Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5331443/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Pancreatic diseases, usually including various pancreatitis, pancreatic cancer and pancreatic cysts, present great challenges to the global health care system. Abnormal lipid profiles are common in these pancreatic diseases, suggesting the lipid-lowering medications may have potential effects on them. However, given the current evidence, the effects of lipid-lowering drugs on pancreatic diseases are inconsistent. Therefore, this study employs drug-targeted Mendelian randomization to investigate the causal relationships between hypocholesterolemic drugs (statins, ezetimibe and PCSK9 inhibitors) and various pancreatic diseases. The findings of our results indicate significant associations between the genetically proxied inhibition of HMGCR and decreased risks of chronic pancreatitis and pancreatic cysts, while PCSK9 inhibition is associated with an increased risk of alcoholic chronic pancreatitis. In addition, NPC1L1 inhibition is linked to an increased risk of pancreatic cysts and benign pancreatic tumors. These results provide insights for screening personalized medications for pancreatic diseases, highlighting the potential benefits of statins in pancreatitis and its complication and the need for caution when prescribing specific lipid-lowering drugs to patients predisposed to pancreatic conditions. Health sciences/Diseases Health sciences/Medical research Health sciences/Risk factors Pancreatic diseases Hypocholesterolemic drugs Statins Mendelian randomization Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Despite great advances in diagnostic methods and more effective treatments, pancreatic diseases remain sparsely understood, costly, and difficult to manage[ 1 ]. Acute pancreatitis (AP) is a leading cause of gastrointestinal hospitalization globally, imposing significant economic burdens[ 2 ]. Chronic pancreatitis (CP), usually developing from recurrent episodes of non-gallstone acute pancreatitis (that is, due to alcohol misuse), severely impacts quality of patients’ life[ 3 ]. Pancreatic cancer (PC) is one of the most lethal cancers, with a 5-year survival rate under 10%, and its incidence is increasing, potentially making it the second leading cause of cancer death by 2030[ 4 – 6 ]. Owing to the complex classification and causes, diagnosing and managing pancreatic cysts remains a significant challenge, developing into one of the most controversial fields in digestive disease[ 7 ]. Usually, abnormal lipid profiles are closely associated with these pancreatic diseases. Hyperlipidemia is an important but underrecognized cause of AP and recurrent acute pancreatitis (RAP). Hypertriglyceridemic pancreatitis is a common cause of AP in people with high TG levels [≥ 500 mg/dL (or ≥ 5.65 mmol/L)], while decreased high-density lipoprotein-cholesterol (HDL-C) is associated with high risk of severe AP and there is a U-shape association between low-density lipoprotein-cholesterol (LDL-C) levels and severe AP[ 8 , 9 ]. Similarly, hyperlipidemia can also lead to CP[ 10 ] and dyslipidemia is implicated in the development of cancers, including PC[ 11 , 12 ]. Thus, these results suggest that regulating lipid metabolism may have the potential to treat the mentioned pancreatic diseases. Nonetheless, it is still unclear about the relationship between dyslipidemia and pancreatic cysts. Lipid-lowering drugs, including 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors (commonly known as statins), Niemann‒Pick C1-Like 1 (NPC1L1) inhibitors (such as ezetimibe), and proprotein convertase subtilisin/keexin type 9 (PCSK9) inhibitors, are the most widely used drugs for the treatment of hypercholesterolemia and primary/secondary prevention of cardiovascular disease[ 13 – 15 ]. Except for regulating lipid metabolism, these drugs, particularly statins, plus the pleiotropy of anti-inflammation, anti-fibrosis and anti-oxidation[ 16 ], suggesting the potential ability to protect against pancreatitis and pancreatic tumors. Unfortunately, the results from observational studies are not always consistent. On the basis of previous case reports, statins were once considered a possible risk factor for drug-related pancreatitis[ 17 ]. However, several recent population-based observational studies have shown that statins are not associated with an increased risk of AP and even have a protective effect[ 18 – 21 ]. In addition, statins have been demonstrated to delay the progression of CP in animal models[ 22 ]. Similar to pancreatitis, such a controversial phenomenon has been observed in the relationship between statins and PC[ 23 – 27 ]. Usually, pancreatic cysts are mainly classified as pancreatic pseudocysts, pancreatic cystic neoplasms (PCNs), etc., and therein, postpancreatitis pseudocyst is the most common pancreatic cysts type, while mucinous cystic neoplasms (MCNs) and main pancreatic duct intraductal papillary mucinous neoplasms (IPMNs) have high malignant potential[ 28 ]. Currently, there is no feasible drug treatment option for pancreatic cysts. A recent cohort study demonstrated the association between statin usage and a reduced risk of postpancreatitis diabetes mellitus (PPDM)[ 29 ], indicating that statins may have potentially protective effects on chronic complications of pancreatitis. However, the effect of statins on pancreatic cyst is unknown. To the best of our knowledge, there is no sufficient evidence to suggest that PCSK9 or NPC1L1 inhibitors are directly associated with these pancreatic diseases. Therefore, given the conflicting and insufficient evidence, further research is needed to determine the relationship between the use of lipid-lowering drugs and the risk of these common pancreatic diseases. Mendelian randomization (MR) is a method that employs single-nucleotide polymorphisms (SNPs) as proxies for specific exposures to determine their causal effects on disease outcomes[ 30 ]. Given that genetic variants are arbitrarily assigned along with chromosome meiosis during conception, MR studies minimize common confounding biases observed in observational studies. By analyzing the variations in genes responsible for coding drug-targeted proteins, MR can provide valuable insights into the potential clinical effects related to these drugs[ 31 ]. Therefore, in this study, we aim to employ an MR design to explore the causal relationship between three lipid-lowering drug targets (HMGCR, NPC1L1, and PCSK9) and various pancreatic diseases, such as various pancreatitis, benign or malignant pancreatic tumors and pancreatic cysts, thereby setting foundation for the subsequent research on lipid-lowering drug strategies in pancreatic diseases. Methods Instrumental variables (IVs ) selection In this study, genome-wide association study (GWAS) data for LDL-C were obtained from the Medical Research Council-Integrative Epidemiology Unit (MRC-IEU) GWAS database (https://gwas.mrcieu.ac.uk/), specifically from the GWAS ID ieu-b-110, which includes data from 440,546 European individuals. Genetic variants targeting HMGCR , PCSK9 , and NPC1L1 were used as IVs to simulate the effects of lipid-lowering drugs on LDL-C reduction. The selection of IVs was based on their significant genome-wide association with LDL-C ( P < 5E-08) and their location within ±100 kb of the HMGCR / PCSK9 / NPC1L1 loci (Figure 1). To mitigate the impact of substantial linkage disequilibrium (LD) on the results, an LD threshold (r 2 < 0.3) was set. SNPs with an F statistic greater than 30 indicated a strong association between the SNP and the exposure; therefore, SNPs with an F statistic greater than 30 were retained. The F statistic was calculated via the formula F = Beta^2/SE^2. MR analysis requires that SNPs are not directly related to the outcome and are not influenced by confounding factors outside of the exposure of interest. Given that our study investigated three related drug targets, a Bonferroni-corrected P value threshold of less than 0.017 (0.05/3) was used to identify significant evidence. Outcome Data Sources We utilized data on AP, CP, alcoholic acute pancreatitis (AAP), alcoholic chronic pancreatitis (ACP), benign/malignant pancreatic tumors and pancreatic cysts as outcomes for MR analysis, with coronary heart disease (CHD) serving as a positive control. The outcome data, except for those for pancreatic cysts, are available from the MRC-IEU GWAS database (https://gwas.mrcieu.ac.uk/). Data for pancreatic cysts were sourced from the GWAS catalog (https://www.ebi.ac.uk/), as detailed in Table 1. There was no overlap between the exposure cohort (UK Biobank) and the outcome cohort. Table 1. Detailed Information on the Studies and Consortia used . Trait Dataset Resource PMID/IOD Ancestor Year Sex Sample Size LDL cholesterol ieu-b-110 UK BioBank 32203549 European 2020 Males and Females 440546 Coronary heart disease ieu-a-7 CARDIoGRAMplusC4D 26343387 Mixed 2015 Males and Females 184305 Acute pancreatitis ebi-a-GCST90018789 EBI GWAS Catalog 34594039 European 2021 _ 479902 Chronic pancreatitis ebi-a-GCST90018821 EBI GWAS Catalog 34594039 European 2021 _ 477528 Alcohol-induced chronic pancreatitis finn-b-ALCOPANCCHRON FinnGen consortium FinnGen consortium (https://www.finngen.fi/fi) European 2021 Males and Females 218792 Acohol-induced acute pancreatitis finn-b-ALCOPANCACU FinnGen consortium FinnGen consortium (https://www.finngen.fi/fi) European 2021 Males and Females 218792 Pancreatic pseudocyst ebi-a-GCST90044206 EBI GWAS Catalog 34737426 European 2021 _ 456348 Pancreatic Malignant Tumour ebi-a-GCST90018893 EBI GWAS Catalog 34594039 European 2021 _ 476245 Pancreatic Benign Tumour finn-b-CD2_BENIGN_PANCREAS FinnGen consortium FinnGen consortium (https://www.finngen.fi/fi) European 2021 Males and Females 218792 Statistical analysis Summary data-based Mendelian randomization ( SMR) and sensitivity analysis To further evaluate the relationship between lipid-lowering drug targets and pancreatic diseases, we applied the SMR method to the significant positive results, utilizing eQTLs and summary data from GWAS. The magnitude of heterogeneity in the findings was tested via the heterogeneity in dependent instruments (HEIDI) tool ( P < 0.01 indicated pleiotropy, suggesting that the observed associations might be due to LD). MR and sensitivity analysis In the inverse-variance weighted (IVW) MR analysis, we focused on genetic variants related to LDL-C levels as IVs. SNPs with an F statistic greater than 30 were included to ensure robust instrument-exposure correlation. To confirm that the selected drug targets did not influence pancreatic disease outcomes through other risk factors, we employed various analytical methods, including IVW, weighted median, and MR Egger. The fixed-effects model of IVW was primarily used for assessment, as it provides reliable causal estimates even in the presence of heterogeneity. To assess heterogeneity and pleiotropy comprehensively and ensure the robustness of the findings, particularly given that outcomes are not influenced by other risk factors associated with exposure, we used Cochran's Q statistic and MR‒Egger regression (intercept). When significant heterogeneity ( P < 0.05) was detected, a multiplicative random effects IVW method was adopted. In the case of observed pleiotropy (intercept P < 0.05), MR‒Egger regression was used as the primary analysis method. The positive control analysis for CHD was performed via the same methods as previously described. SMR analysis was conducted via software version 1.03 (for details, see https://cnsgenomics.com/software/smr/#Overview). Additionally, two-sample data analysis was performed via R version 4.4.0 with the TwoSampleMR package (0.61). Results Association of HMGCR with Pancreatic Diseases For the IVW MR analysis, we utilized 19 IVs related to the HMGCR target. The analysis revealed a significant association between the HMGCR genetic variant and an increased risk of CP (OR, 2.05; 95% CI: 1.07–3.91; P = 0.0298). Additionally, simulated genetic variations in HMGCR were significantly associated with an increased risk of pancreatic cysts (OR, 7.56; 95% CI: 1.55–36.82; P = 0.0123), with the Bonferroni-corrected P values remaining significant (Figure2). Association of PCSK9 with Pancreatic Diseases For the PCSK9 target, 33 IVs were analyzed. The IVW MR analysis indicated a significant association between the PCSK9 genetic variant and a decreased risk of ACP (OR, 0.56; 95% CI: 0.34–0.92; P = 0.023) (Figure 3). This protective effect suggests potential benefits of PCSK9 inhibition in reducing the risk of CP associated with alcohol consumption. However, significant pleiotropy was observed in the MR analysis of PCSK9 with AP ( P = 0.003), ACP ( P = 0.04), and AAP ( P = 0.00059), indicating that some associations might be influenced by factors other than direct genetic effects on LDL-C levels (Figure 3). Association of NPC1L1 with Pancreatic Diseases The analysis included 6 IVs related to the NPC1L1 target. The IVW MR analysis demonstrated a significant association between NPC1L1 inhibition and an increased risk of pancreatic cysts (OR, 7.56; 95% CI: 1.55--36.82; P = 0.0123), with the Bonferroni-corrected P values remaining significant. NPC1L1 drug targets were associated with a reduced risk of benign pancreatic tumors (OR, 0.01; 95% CI: 0.00--0.84; P = 0.0415) (Figure 4). Sensitivity Analyses To ensure the robustness of our findings, we conducted sensitivity analyses via MR‒Egger regression and Cochran's Q statistic. The MR‒Egger intercept tests did indicate pleiotropy for the PCSK9 target. However, MR-PRESSO did not detect any outliers, and the results of the MR‒Egger analysis were consistent with those obtained via the weighted median method and the standard IVW method. This consistency across different analytical methods reinforces the reliability of the causal estimates for PCSK9, despite the observed pleiotropy. For HMGCR and NPC1L1, the MR‒Egger intercept tests did not indicate significant pleiotropy, and Cochran's Q test revealed no evidence of heterogeneity for the outcomes (all P > 0.05), further supporting the validity of these findings (Table 2). Table2 Association between lipid-lowering drugs and pancreatic diseases Exposure Outcome nSNP MR Egger Weighted median IVW Heterogeneity Pleiotropy SMR OR 95%CI P OR 95%CI P OR 95%CI P Cochrane’s Q Q_ pval P MRPRESSO Egger_Intercept P Pleiotropy P SMR P HEIDI HMGCR Coronary heart disease 19 1.93 1.07-3.48 0.04 1.61 1.27-2.04 7.239E-05 1.62 1.36-1.93 8.294E-08 16.7175 0.542602 0.58 -0.00805 0.55 Acute pancreatitis 19 2.51 0.71-8.91 0.17 1.38 0.83-2.29 0.21 1.43 0.97-2.10 0.069 16.02 0.59 0.65 -0.025 0.37 Chronic pancreatitis 19 0.93 0.11-8.17 0.95 1.88 0.80-4.41 0.15 2.05 1.07-3.91 0.03 21.04 0.28 0.34 0.036 0.47 Acohol-induced acute pancreatitis 19 0.69 0.02-29.17 0.85 0.41 0.08-1.96 0.26 0.39 0.12-1.24 0.11 9.02 0.96 0.96 -0.025 0.76 Alcohol-induced chronic pancreatitis 19 1.1 0.07-17.84 0.95 1.72 0.58-5.09 0.33 1.36 0.59-3.15 0.47 19.67 0.35 0.42 0.00938 0.88 Benign neoplasm: Pancreas 19 0.05 0.00-26.06 0.36 0.37 0.03-4.56 0.43 0.3 0.04-2.05 0.22 8.51 0.97 0.98 0.079 0.57 Pancreatic Malignant Tumour 19 0.65 0.08-5.38 0.7 0.58 0.26-1.29 0.18 0.55 0.29-1.03 0.063 9.91 0.93 0.95 -0.0081 0.86 Cyst and Pseudocyst of Pancreas 19 6.17 0.04-1076 0.5 9.29 1.08-79.94 0.04 7.56 1.55-36.82 0.0123 16.21 0.58 0.6 0.009004 0.94 0.048 0.109 PCSK9 Coronary heart disease 28 2.07 1.55-2.77 4.463E-05 2.13 1.69-2.68 1.477E-10 2.3 1.95-2.70 7.204E-24 26.5 0.49 0.58 0.004765 0.4 Acute pancreatitis 33 0.7 0.49-1.02 0.071 0.76 0.54-1.07 0.12 1.09 0.83-1.42 0.55 34.6 0.34 0.25 0.029612 0.003158 Chronic pancreatitis 33 0.85 0.49-1.49 0.581 0.82 0.47-1.42 0.48 1.04 0.7-1.54 0.85 20.47 0.94 0.942 0.014 0.34 Acohol-induced acute pancreatitis 29 0.46 0.19-1.16 0.111 0.74 0.30-1.80 0.51 1.55 0.68-3.54 0.299 41.04 0.053 0.06 0.107135 0.000592 Alcohol-induced chronic pancreatitis 29 0.35 0.19-0.66 0.0032 0.44 0.24-0.82 0.0094 0.56 0.34-0.92 0.023 32.19 0.27 0.283 0.0413 0.04 Benign neoplasm: Pancreas 29 1.01 0.22-4.63 0.993 1.21 0.30-4.93 0.79 2.14 0.69-6.97 0.19 14.67 0.98 0.98 0.067 0.16 Pancreatic Malignant Tumour 33 0.93 0.47-1.84 0.83 1.01 0.52-1.96 0.97 1.24 0.79-1.95 0.35 20.75 0.94 0.918 0.018 0.273 Cyst and Pseudocyst of Pancreas 29 0.93 0.16-5.28 0.94 1.59 0.30-8.39 0.58 1.71 0.53-5.48 0.37 13.98 0.987 0.99 0.0378 0.363 0.660 0.628 NPC1L1 Coronary heart disease 6 1.03 0.26-4.12 0.97 2.01 1.17-3.44 0.0109 2.19 1.41-3.39 0.00049 1.81 0.87 0.87 0.018786 0.325 Acute pancreatitis 6 0.33 0.01-8.58 0.54 0.41 0.12-1.38 0.15 0.49 0.18-1.35 0.167 2.29 0.81 0.85 0.009852 0.81 Chronic pancreatitis 6 0..37 0.00-48.85 0.71 0.32 0.05-1.9 0.21 0.41 0.09-1.84 0.243 2.79 0.73 0.77 0.002118 0.97 Acohol-induced acute pancreatitis 6 1 0.00-5171 0.999 0.07 0.00-1.64 0.0982 0.08 0.01-1.16 0.0643 3.76 0.58 0.72 -0.06527 0.57 Alcohol-induced chronic pancreatitis 6 16.54 0.01-33832 0.51 0.8 0.09-7.51 0.85 0.91 0.09-9.11 0.934 7.68 0.17 0.3 -0.0745 0.48 Benign neoplasm: Pancreas 6 0.59 0.00-870064 0.95 0.01 0.00-2.19 0.096 0.01 0.00-0.84 0.0415 0.892 0.97 0.96 -0.10594 0.58 Pancreatic Malignant Tumour 6 0.42 0.00-114.56 0.78 0.73 0.08-6.42 0.774 0.76 0.13-4.35 0.76 1.87 0.87 0.85 0.014474 0.84 Cyst and Pseudocyst of Pancreas 4 0 0.00-463635175 0.45 0 0-0.12 0.009 0 0.00-0.02 0.00071 1.545072 0.67 0.69 0.18439 0.7 0.0493 0.813 SMR Analysis SMR analysis via summary data revealed significant associations between NPC1L1 inhibition ( P = 0.0493, HEIDI = 0.812842) and HMGCR inhibition ( P = 0.047, HEIDI = 0.108) and the risk of pancreatic cysts. The HEIDI tests suggested no pleiotropy, indicating that the associations were likely direct effects of the genetic variants on pancreatic cyst risk. These results support the findings from the IVW MR analysis and highlight the potential for NPC1L1 and HMGCR inhibitors to influence pancreatic cyst formation. Discussion In this study, MR analysis was applied to investigate the causal relationships of genetic variants in three common lipid-lowering drug targets (HMGCR, PCSK9 and NPC1L1) with several major pancreatic diseases. Our preliminary MR analysis provided credible evidence to support the potential protective effects of statins on CP and pancreatic cysts, the relationship between PCSK9 inhibition and a high risk of ACP and the positive correlation between the genetically proxied inhibition of NPC1L1 and high risks of pancreatic cysts and other benign pancreatic tumors, enriching the current literature and providing new insights into the safety and clinical decisions of these lipid-lowering drugs. We first found a causal association between HMGCR genetic variants and CP, with no heterogeneity or pleiotropic effects, indicating that this study provides strong evidence for the causal effect of statin use on CP. Our observations seem to be consistent with those of previous in vitro and in vivo experiments. Statins have been demonstrated to have pleiotropic effects, such as anti-inflammatory, antifibrotic and antioxidative effects[ 32 – 34 ], suggesting the potential ability to treat CP. To confirm this possibility, Wei L et al. [ 22 ] used a mouse model and successfully demonstrated that statin treatment delayed the progression of CP. Furthermore, lovastatin was found to successfully inhibit the activation of pancreatic stellate cells, which may prevent fibrosis and the inflammatory response in CP[ 35 ]. Interestingly, a multicenter three-blind randomized controlled trial confirmed that simvastatin prevented RAP, an intermediate stage in the pathogenesis of CP[ 21 , 36 ]. Nonetheless, the directly causal relationship of statin use with decreased CP risk in the population remains unclear. The latest evidence suggests that statins can inhibit chronic inflammation by blocking the TBK1-IRF3-IL-33 signaling axis, effectively reducing CP risk in mice and humans[ 37 ]. These finding and our MR results are highly important, as they suggest that statins may turn to be a safe, effective, and easily available treatment strategy for the prevention of CP. In addition, our results revealed that the predicted PCSK9 variant was associated with a reduced risk of ACP, although there was no causal association with CP overall. These findings are striking and explainable. To the best of our knowledge, alcohol abuse is a predominant cause of CP worldwide, especially in Western countries[ 38 ]. Interestingly, the incidence of CP resulting from different etiologies varies across different populations, and the related disease complications of CP also vary. For example, ACP is associated mainly with local inflammatory complications, such as increased risks of pseudocysts and pseudoaneurysms, whereas smoking is associated mainly with fibrotic complications (pancreatic duct lesions, biliary stenosis, etc.) and is negatively associated with inflammation[ 39 ]. Interestingly, Lebeau, Paul F et al. have demonstrated that PCSK9 deficiency can promote inflammation[ 40 ], which seems to explain our findings revealing a causal association of genetically proxied PCSK9 inhibition with elevated risk of ACP. Nonetheless, the role of PCSK9 in the development of general CP is unknown, and, in contrast to what we discussed earlier, the effects of PCSK9 inhibition on inflammatory and fibrotic responses are actually inconsistent in different backgrounds[ 41 – 43 ]. Given this, our results may provide a better explanation for the causal relationship between genetically proxied PCSK9 inhibition and a high risk of ACP from a genetic perspective, indicating that PCSK9 inhibitors should be used carefully when prescribing lipid-lowering drugs in chronic alcoholism patients. However, our findings have suggested that there is no significant causal relationship between PCSK9 and CP risk. To note, we simulated the PCSK9 variant by genetic instrumentals to predict its relationship with pancreatitis, which is an original effect. In other words, there are different causal relationships between genetically proxied PCSK9 inhibition and various pancreatitis, which may attribute to different genetic milieu in different diseases, while the causal relationships in real world may be long-term and more complex. Interestingly, our results suggest that genetic variants in HMGCR are associated with a high risk of pancreatic cysts while NPC1L1 genetic variants are negatively related to them, which are important to the implications for the clinical management of pancreatic cysts. To our best knowledge, there was no direct evidence to show any causal association between commonly-used medications and the risks of pancreatic cysts, our results are the first to indicate the causal relationships of lipid-lowering medications with pancreatic cysts.. Postpancreatitis pseudocyst is mostly common in histological classification of pancreatic pseudocyst, characterized as an inflammatory cyst preserving abnormal fluid in or around the pancreas[ 28 ]. Conversely, pseudocyst is also one of the most common sequela of pancreatitis. A recent cohort study demonstrated the association between statin usage and a reduced risk of PPDM, indicating that statins may have potentially protective effects on chronic complications of AP or CP[ 29 ]. Additionally, the anti-fibrotic and anti-inflammatory effects of statins may have inhibitory effects on cyst formation[ 16 ]. On the other hand, PCNs, including IPMNs and MCNs, are considered malignant precursors of PC[ 44 ], while few previous studies have focused on the correlation of statins with PCNs. Notably, a recent multi-omics study found that IPMN profiles showed significant lipid pathway alterations[ 45 ], suggesting that regulating abnormal lipid profiles may have the potential benefits. In addition, the mutations of TP53 and the Kirsten rat sarcoma viral oncogene homolog (KRAS) are the most important mutations associated with neoplastic cysts[ 46 ], while statins have been demonstrated to induce the degradation of mutant TP53 and KRAS by inhibiting the mevalonate pathway[ 47 ], suggesting a potential association of statins with PCNs. These findings provide indirect support for statins’ potential protective role in pancreatic cysts. Aligned well with these findings, the findings from our results are the first to demonstrate an association between an easily available and inexpensive strategy, statins, and a reduced risk of pancreatic cysts, though it requires further experiments and clinical studies to confirm it. Currently, surgical strategies are mainly adopted for the treatment of pancreatic cysts, while the pharmacological and toxicological effects of drugs on pancreatic cysts are an important but still unsolved problem. Converse to statins, we find that NPC1L1 inhibitors may increase the risk of pancreatic cysts and benign pancreatic tumors, which is a mysterious area that has not yet been reported. This can generate hypotheses for future studies and provide a possible pharmacological treatment strategy for clinicians. Our results seem to give some hints that clinicians should pay more attention to the use of statins, and take more caution with NPC1L1 inhibitors when developing lipid-regulating drug strategies for patients at high risk of developing pancreatic cysts. More importantly, these findings also inform longitudinal prospective cohort studies to examine the use of these two lipid-lowering drugs and their relationship with pancreatic cysts and advise randomized controlled trials to examine long-term outcomes. The causal relationship of lipid-lowering drugs, especially statins, with AP or PC has attracted much attention, and inconsistent results have been obtained in different observational studies. Whether in AP or PC, the causal associations of statins and each one of the two diseases ranged from elevated[ 48 , 49 ] or decreased[ 20 , 24 , 25 ] risk to no significant association[ 26 , 27 , 50 – 52 ]. However, it is difficult to confidently obtain causal relationships from observational or other traditional epidemiological studies owing to the potential residual impact of incompletely measured confounding or bias. To the best of our knowledge, this study is the first to employ drug target MR analysis to provide new insights into the causal relationships between lipid-lowering drugs and AP and PC, enriching the current literature. Although we did not find a causal relationship between the three lipid-lowering drug target genetic instruments and AP or PC, our MR analysis, by genetic verification, eliminated confounders and bias as much as possible. Nonetheless, other underlying associations are unclear and require further investigation. There are several limitations to our research. First, as with all MR studies, IV assumptions are not empirically verifiable. It is unable to completely eliminate the possibility of confounding bias and/or horizontal pleiotropy, although we performed multiple sensitivity analyses to scrutinize the research hypotheses of MR. Second, it is worth noting that the eQTLs and GWAS data used in this study were from European populations, where cholelithiasis and alcohol are the main causes of AP and CP, whereas in China, hyperlipidemic acute pancreatitis has become non-negligible. Therefore, validation of the generality of our results in broader population cohorts is needed, including conducting similar MR analyses in different population cohorts and exploring potential genetic and environmental interactions. Conclusion On the basis of our MR analysis, the genetically proxied inhibition of HMGCR was associated with an increased risk of CP and pancreatic cysts, the genetically proxied inhibition of PCSK9 was associated with a decreased risk of alcohol-related CP, and the NPC1L1 genetically proxied inhibition were associated with decreased risks of benign pancreatic tumors and pancreatic cysts. Our findings strongly support the use of statins as a strategy to prevent the occurrence and development of CP. Moreover, our results provide advice to clinicians on clinical decision-making -- statins should be used rather than NPC1L1 inhibitors as possible when people at high risk of pancreatic cysts need lipid-lowering strategies, thereby achieving more personalized therapy. In addition, the findings indicate that the genetic variants of the three lipid-lowering drugs are not significantly causally related to AP or PC, further genetically verifying their safety for these pancreatic diseases. Abbreviations AP Acute pancreatitis CP Chronic pancreatitis PC Pancreatic cancer RAP Recurrent acute pancreatitis LDL-C Low density lipoprotein-cholesterol LDLR Low density lipoprotein receptor HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase NPC1L1 Niemann-Pick C1-Like 1 PCSK9 Proprotein convertase subtilisin/keexin type 9 PCNs Pancreatic cystic neoplasms MCNs Mucinous cystic neoplasms IPMNs Intraductal papillary mucinous neoplasms PPDM Post pancreatitis diabetes mellitus MR Mendelian randomization SNPs Single-nucleotide polymorphisms GWAS Genome-wide association study MRC-IEU Medical Research Council-Integrative Epidemiology Unit IVs Instrumental variables LD Linkage disequilibrium HEIDI Heterogeneity in dependent instruments AAP Alcoholic acute pancreatitis ACP Alcoholic chronic pancreatitis CHD Coronary heart disease SMR Summary data-based Mendelian Randomization IVW Inverse-variance weighted KRAS Kirsten rat sarcoma viral oncogene homolog Declarations A cknowledgments We acknowledge the participants and investigators of the UK Biobank and FinnGen studies. Author Contributions Yong-Chuan Chen and Can-E Tang designed the study; Ge Yang conducted the data analysis; Ge Yang and Yi-Zhuo Feng prepared all the figures and tables; Yi-Zhuo Feng and Ge Yang edited the manuscript. Yan-Jiao Ou, Hong Zhang, Can-E Tang and Yong-Chuan Chen reviewed and revised the manuscript. All the authors contributed to the article and approved the submitted version. Funding This study was supported by the Natural Science Foundation of Hunan Province (2024JJ5611) and the National Natural Science Foundation of China (82370642). Availability of Data and Materials The genome-wide association study (GWAS) data for LDL-C used in this study were obtained from the Medical Research Council-Integrative Epidemiology Unit (MRC-IEU) GWAS database under GWAS ID ieu-b-110, accessible at https://gwas.mrcieu.ac.uk/. Data on acute pancreatitis (AP), chronic pancreatitis (CP), alcoholic acute pancreatitis (AAP), alcoholic chronic pancreatitis (ACP), benign/malignant pancreatic tumors, and coronary heart disease (CHD) were also sourced from the MRC-IEU GWAS database, which is accessible at https://gwas.mrcieu.ac.uk/. Data for pancreatic cysts were obtained from the GWAS Catalog, accessible at https://www.ebi.ac.uk/gwas/. All relevant data supporting the findings of this study are included within the article and its supplementary materials. For any additional information or data requests, please contact the corresponding authors. Ethics Approval and Consent to Participate All analyses were performed on anonymized summary statistics from published GWAS with appropriate institutional review board approval. Separate institutional review board approval was not required for this study. Consent for Publication Not applicable. Competing Interests The authors declare that there are no competing interests. The research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. References Xiao, A. Y. et al. Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol. Hepatol. 1 , 45 (2016). Peery, A. F. et al. Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2021. GASTROENTEROLOGY 162 621 (2022). Hines, O. J. & Pandol, S. J. Management of chronic pancreatitis. BMJ . 384 , e70920 (2024). Siegel, R. L., Giaquinto, A. N. & Jemal, A. Cancer statistics, 2024. CA Cancer J. Clin. 74 , 12 (2024). Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. CANCER RES. 74 , 2913 (2014). Park, W., Chawla, A. & O'Reilly, E. M. Pancreatic Cancer: A Review. JAMA 326 851 (2021). Gardner, T. B., Park, W. G. & Allen, P. J. Diagnosis and Management of Pancreatic Cysts. GASTROENTEROLOGY 167 454 (2024). Yang, A. L. & McNabb-Baltar, J. Hypertriglyceridemia and acute pancreatitis. PANCREATOLOGY . 20 , 795 (2020). Hong, W. et al. Relationship between low-density lipoprotein cholesterol and severe acute pancreatitis (the lipid paradox). THER. CLIN. RISK MANAG . 14 , 981 (2018). Truninger, K., Schmid, P. A., Hoffmann, M. M., Bertschinger, P. & Ammann, R. W. Recurrent acute and chronic pancreatitis in two brothers with familial chylomicronemia syndrome. PANCREAS 32 215 (2006). Yin, X. et al. Lipid metabolism in pancreatic cancer: emerging roles and potential targets. Cancer Commun. (Lond) . 42 , 1234 (2022). Revilla, G. et al. HDL and endocrine-related cancer: From pathogenic mechanisms to therapies. SEMIN CANCER BIOL. 73 , 134 (2021). Pirillo, A., Catapano, A. L. & Norata, G. D. Niemann-Pick C1-Like 1 (NPC1L1) Inhibition and Cardiovascular Diseases. CURR. MED. CHEM. 23 , 983 (2016). Stein, E. A. & Raal, F. J. Lipid-Lowering Drug Therapy for CVD Prevention: Looking into the Future. CURR. CARDIOL. REP. 17 , 104 (2015). Dadu, R. T. & Ballantyne, C. M. Lipid lowering with PCSK9 inhibitors. NAT. REV. CARDIOL. 11 , 563 (2014). Kavalipati, N., Shah, J., Ramakrishan, A. & Vasnawala, H. Pleiotropic effects of statins. Indian J. Endocrinol. Metab. 19 , 554 (2015). Badalov, N. et al. Drug-induced acute pancreatitis: an evidence-based review. Clin. Gastroenterol. Hepatol. 5 648 , 644 (2007). Preiss, D. et al. Lipid-modifying therapies and risk of pancreatitis: a meta-analysis. JAMA . 308 , 804 (2012). Talukdar, R. & Vege, S. S. Acute pancreatitis. Curr. Opin. Gastroenterol. 31 , 374 (2015). Wu, B. U., Pandol, S. J. & Liu, I. L. Simvastatin is associated with reduced risk of acute pancreatitis: findings from a regional integrated healthcare system. GUT . 64 , 133 (2015). Cardenas-Jaen, K. et al. Simvastatin in the Prevention of Recurrent Pancreatitis: Design and Rationale of a Multicenter Triple-Blind Randomized Controlled Trial, the SIMBA Trial. Front. Med. (Lausanne) . 7 , 494 (2020). Wei, L., Yamamoto, M., Harada, M. & Otsuki, M. Treatment with pravastatin attenuates progression of chronic pancreatitis in rat. LAB. INVEST. 91 , 872 (2011). Bagheri, H., Adeli, O. A., Heidari-Soureshjani, S., Azadegan-Dehkordi, Z. & Mt, S. C. The Relationship between Statin Intake and Risk of Pancreatic Cancer: A Systematic Review and Meta-Analysis. Curr. Drug Res. Rev. (2024). Saito, K. et al. Exposure and Pancreatic Cancer Incidence: A Japanese Regional Population-Based Cohort Study, the Shizuoka Study. Cancer Prev. Res. (Phila) . 14 , 863 (2021). Kirkegard, J., Lund, J. L., Mortensen, F. V. & Cronin-Fenton, D. Statins and pancreatic cancer risk in patients with chronic pancreatitis: A Danish nationwide population-based cohort study. INT. J. CANCER . 146 , 610 (2020). Bang, U. C., Watanabe, T. & Bendtsen, F. The relationship between the use of statins and mortality, severity, and pancreatic cancer in Danish patients with chronic pancreatitis. Eur. J. Gastroenterol. Hepatol. 30 , 346 (2018). Hamada, T. et al. Statin use and pancreatic cancer risk in two prospective cohort studies. J. GASTROENTEROL. 53 , 959 (2018). Sahani, D. V. et al. Cystic pancreatic lesions: classification and management. J. AM. COLL. RADIOL. 6 , 376 (2009). Thiruvengadam, N. R. et al. Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis. Clin. Gastroenterol. Hepatol. 21 , 1214 (2023). Davey, S. G. & Hemani, G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. HUM. MOL. GENET. 23 , R89 (2014). Gill, D. et al. Mendelian randomization for studying the effects of perturbing drug targets. Wellcome Open. Res. 6 , 16 (2021). Solheim, S., Seljeflot, I., Arnesen, H., Eritsland, J. & Eikvar, L. Reduced levels of TNF alpha in hypercholesterolemic individuals after treatment with pravastatin for 8 weeks. ATHEROSCLEROSIS . 157 , 411 (2001). Li, C. et al. Pravastatin treatment attenuates interstitial inflammation and fibrosis in a rat model of chronic cyclosporine-induced nephropathy. Am. J. Physiol. Ren. Physiol. 286 , F46 (2004). Moriyama, T. et al. Fluvastatin suppresses oxidative stress and fibrosis in the interstitium of mouse kidneys with unilateral ureteral obstruction. KIDNEY INT 59 (2001). (2095). Jaster, R., Brock, P., Sparmann, G., Emmrich, J. & Liebe, S. Inhibition of pancreatic stellate cell activation by the hydroxymethylglutaryl coenzyme A reductase inhibitor lovastatin. BIOCHEM. PHARMACOL. 65 , 1295 (2003). Machicado, J. D. & Yadav, D. Epidemiology of Recurrent Acute and Chronic Pancreatitis: Similarities and Differences. Dig. Dis. Sci. 62 , 1683 (2017). Park, J. H. et al. Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression. NAT. COMMUN. 15 , 4099 (2024). Bang, U. C., Benfield, T., Hyldstrup, L., Bendtsen, F. & Beck, J. J. Mortality, cancer, and comorbidities associated with chronic pancreatitis: a Danish nationwide matched-cohort study. GASTROENTEROLOGY . 146 , 989 (2014). Agarwal, S. et al. Natural course of chronic pancreatitis and predictors of its progression. PANCREATOLOGY . 20 , 347 (2020). Lebeau, P. F. et al. Pcsk9 knockout exacerbates diet-induced non-alcoholic steatohepatitis, fibrosis and liver injury in mice. JHEP Rep. 1 , 418 (2019). D'Onofrio, N. et al. SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells. THERANOSTICS . 13 , 531 (2023). Dong, X. C. Sirtuin 6-A Key Regulator of Hepatic Lipid Metabolism and Liver Health. CELLS-BASEL 12 (2023). Ioannou, G. N. et al. Pcsk9 Deletion Promotes Murine Nonalcoholic Steatohepatitis and Hepatic Carcinogenesis: Role of Cholesterol. Hepatol. Commun. 6 , 780 (2022). de Jong, K. et al. High prevalence of pancreatic cysts detected by screening magnetic resonance imaging examinations. Clin. Gastroenterol. Hepatol. 8 , 806 (2010). Gaiser, R. A. et al. Integrated targeted metabolomic and lipidomic analysis: A novel approach to classifying early cystic precursors to invasive pancreatic cancer. Sci. Rep. 9 , 10208 (2019). Chen, J. C., Beal, E. W., Pawlik, T. M., Cloyd, J. & Dillhoff, M. E. Molecular Diagnosis of Cystic Neoplasms of the Pancreas: a Review. J. GASTROINTEST. SURG. 24 , 1201 (2020). Xu, D. et al. Inhibition of mutant Kras and p53-driven pancreatic carcinogenesis by atorvastatin: Mainly via targeting of the farnesylated DNAJA1 in chaperoning mutant p53. Mol Carcinog 58 (2019). (2052). O'Connor, C. E., Dang, B. Q., Miles, B. & Mackey, J. Statin Therapy and Pancreatitis: A Multi-Institutional Retrospective Analysis. Cureus . 16 , e51723 (2024). Lin, C. M., Liao, K. F., Lin, C. L. & Lai, S. W. Use of Simvastatin and Risk of Acute Pancreatitis: A Nationwide Case-Control Study in Taiwan. J. CLIN. PHARMACOL. 57 , 918 (2017). Poropat, G. et al. Statin use is not associated with an increased risk of acute pancreatitis-A meta-analysis of observational studies. United Eur. Gastroenterol. J. 6 , 1206 (2018). Ba, D. M., Zhang, Y., Chinchilli, V. M. & Maranki, J. Statins exposure and acute pancreatitis: a retrospective cohort study using a large national insurance database. BMJ OPEN 13 e77591 (2023). Simon, M. S. et al. Prospective analysis of association between statins and pancreatic cancer risk in the Women's Health Initiative. Cancer Causes Control . 27 , 415 (2016). Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5331443","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":386035413,"identity":"2d104ef5-beeb-4846-b4e8-7b6fc41ae145","order_by":0,"name":"Ge Yang","email":"","orcid":"","institution":"Southwest Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ge","middleName":"","lastName":"Yang","suffix":""},{"id":386035414,"identity":"809dd9ce-a08a-43de-a440-9cfc39a19e34","order_by":1,"name":"Yizhuo Feng","email":"","orcid":"","institution":"Xiangya Hospital Central South University","correspondingAuthor":false,"prefix":"","firstName":"Yizhuo","middleName":"","lastName":"Feng","suffix":""},{"id":386035415,"identity":"8de25425-f20d-40d8-9789-2bb1b284c4f1","order_by":2,"name":"Yanjiao Ou","email":"","orcid":"","institution":"Southwest Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yanjiao","middleName":"","lastName":"Ou","suffix":""},{"id":386035416,"identity":"ea4eed4a-4996-4cb9-9327-1e4b7fc088c0","order_by":3,"name":"Hong Zhang","email":"","orcid":"","institution":"Renmin Hospital of Wuhan University","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Zhang","suffix":""},{"id":386035417,"identity":"c1b417fd-eb9c-4111-91aa-c08a055af76a","order_by":4,"name":"Can-E Tang","email":"","orcid":"","institution":"Xiangya Hospital Central South University","correspondingAuthor":false,"prefix":"","firstName":"Can-E","middleName":"","lastName":"Tang","suffix":""},{"id":386035420,"identity":"4e1cad98-5b33-48f6-bc06-948edbe245a9","order_by":5,"name":"Yongchuan Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYPACGyjNRryWNAmStRwmQYv8jOzEzzw15+t0p50xYPhQdpiBf3YDfi2MM3I3S/Mcuy1hdjvHgHHGucMMEncO4NfCLJ27jZm3AaKFmbftMIOBRAJ+LWwQLecgWv4So4UHouUARAsjMVok5N9ulpxzLFly2+20goM959J5JG4Q0CLfc3bjhzc1dvxmt5M3PvhRZi3HP4OAFhBg4oEyDoBcSlg9EDD+IErZKBgFo2AUjFgAANFJPs4znG/rAAAAAElFTkSuQmCC","orcid":"","institution":"Southwest Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yongchuan","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-10-25 09:53:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5331443/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5331443/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71632865,"identity":"f0b8b440-f97d-4f36-a535-2582de88b2ba","added_by":"auto","created_at":"2024-12-17 09:47:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":105794,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDesign of the drug-target MR analyses. \u003c/strong\u003eLDL-C: low-density lipoprotein cholesterol; SNP: single nucleotide polymorphism; HMGCR: HMG-CoA reductase; NPC1L1: Niemann-Pick C1-like protein 1; PCSK9: proprotein convertase subtilisin/kexin type 9.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5331443/v1/e4e34e4370cd461c72beca9a.png"},{"id":71632866,"identity":"773bf905-be87-4cc1-bf02-1d8b784e2c65","added_by":"auto","created_at":"2024-12-17 09:47:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":371742,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociationsbetween HMGCR and pancreatic diseases.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5331443/v1/e1a5c27b555b33260e279dc8.png"},{"id":71634497,"identity":"9a3cb833-ded5-4878-bfd4-5d85fecc17f9","added_by":"auto","created_at":"2024-12-17 09:55:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":370987,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociationsbetween PCSK9 and pancreatic diseases.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5331443/v1/1ce3d9a6b462424cff74e347.png"},{"id":71632867,"identity":"bccf6698-804c-4891-9e31-f8b9d297ef58","added_by":"auto","created_at":"2024-12-17 09:47:59","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":371564,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociationsbetween NPC1L1 and pancreatic diseases.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5331443/v1/58c75905522c61e400c646cb.png"},{"id":77433590,"identity":"51b8ed8c-8efd-4f9d-8ec4-61562d342353","added_by":"auto","created_at":"2025-02-28 14:32:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2300272,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5331443/v1/319e3499-2899-42cc-8dec-ef7feaa0a54f.pdf"},{"id":71632862,"identity":"0d15d09c-b32c-4c45-9d56-a21793ac6adc","added_by":"auto","created_at":"2024-12-17 09:47:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":47790,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEMRchecklistfillable.docx","url":"https://assets-eu.researchsquare.com/files/rs-5331443/v1/dca89f481a2a1c34d5dac79c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of Lipid-Lowering Therapy on Pancreatic Health: Insights from Mendelian Randomization","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDespite great advances in diagnostic methods and more effective treatments, pancreatic diseases remain sparsely understood, costly, and difficult to manage[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Acute pancreatitis (AP) is a leading cause of gastrointestinal hospitalization globally, imposing significant economic burdens[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Chronic pancreatitis (CP), usually developing from recurrent episodes of non-gallstone acute pancreatitis (that is, due to alcohol misuse), severely impacts quality of patients\u0026rsquo; life[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Pancreatic cancer (PC) is one of the most lethal cancers, with a 5-year survival rate under 10%, and its incidence is increasing, potentially making it the second leading cause of cancer death by 2030[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Owing to the complex classification and causes, diagnosing and managing pancreatic cysts remains a significant challenge, developing into one of the most controversial fields in digestive disease[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eUsually, abnormal lipid profiles are closely associated with these pancreatic diseases. Hyperlipidemia is an important but underrecognized cause of AP and recurrent acute pancreatitis (RAP). Hypertriglyceridemic pancreatitis is a common cause of AP in people with high TG levels [\u0026ge;\u0026thinsp;500 mg/dL (or \u0026ge;\u0026thinsp;5.65 mmol/L)], while decreased high-density lipoprotein-cholesterol (HDL-C) is associated with high risk of severe AP and there is a U-shape association between low-density lipoprotein-cholesterol (LDL-C) levels and severe AP[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Similarly, hyperlipidemia can also lead to CP[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and dyslipidemia is implicated in the development of cancers, including PC[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Thus, these results suggest that regulating lipid metabolism may have the potential to treat the mentioned pancreatic diseases. Nonetheless, it is still unclear about the relationship between dyslipidemia and pancreatic cysts.\u003c/p\u003e \u003cp\u003eLipid-lowering drugs, including 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors (commonly known as statins), Niemann‒Pick C1-Like 1 (NPC1L1) inhibitors (such as ezetimibe), and proprotein convertase subtilisin/keexin type 9 (PCSK9) inhibitors, are the most widely used drugs for the treatment of hypercholesterolemia and primary/secondary prevention of cardiovascular disease[\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Except for regulating lipid metabolism, these drugs, particularly statins, plus the pleiotropy of anti-inflammation, anti-fibrosis and anti-oxidation[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], suggesting the potential ability to protect against pancreatitis and pancreatic tumors. Unfortunately, the results from observational studies are not always consistent. On the basis of previous case reports, statins were once considered a possible risk factor for drug-related pancreatitis[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, several recent population-based observational studies have shown that statins are not associated with an increased risk of AP and even have a protective effect[\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In addition, statins have been demonstrated to delay the progression of CP in animal models[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Similar to pancreatitis, such a controversial phenomenon has been observed in the relationship between statins and PC[\u003cspan additionalcitationids=\"CR24 CR25 CR26\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Usually, pancreatic cysts are mainly classified as pancreatic pseudocysts, pancreatic cystic neoplasms (PCNs), etc., and therein, postpancreatitis pseudocyst is the most common pancreatic cysts type, while mucinous cystic neoplasms (MCNs) and main pancreatic duct intraductal papillary mucinous neoplasms (IPMNs) have high malignant potential[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Currently, there is no feasible drug treatment option for pancreatic cysts. A recent cohort study demonstrated the association between statin usage and a reduced risk of postpancreatitis diabetes mellitus (PPDM)[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], indicating that statins may have potentially protective effects on chronic complications of pancreatitis. However, the effect of statins on pancreatic cyst is unknown. To the best of our knowledge, there is no sufficient evidence to suggest that PCSK9 or NPC1L1 inhibitors are directly associated with these pancreatic diseases. Therefore, given the conflicting and insufficient evidence, further research is needed to determine the relationship between the use of lipid-lowering drugs and the risk of these common pancreatic diseases.\u003c/p\u003e \u003cp\u003eMendelian randomization (MR) is a method that employs single-nucleotide polymorphisms (SNPs) as proxies for specific exposures to determine their causal effects on disease outcomes[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Given that genetic variants are arbitrarily assigned along with chromosome meiosis during conception, MR studies minimize common confounding biases observed in observational studies. By analyzing the variations in genes responsible for coding drug-targeted proteins, MR can provide valuable insights into the potential clinical effects related to these drugs[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Therefore, in this study, we aim to employ an MR design to explore the causal relationship between three lipid-lowering drug targets (HMGCR, NPC1L1, and PCSK9) and various pancreatic diseases, such as various pancreatitis, benign or malignant pancreatic tumors and pancreatic cysts, thereby setting foundation for the subsequent research on lipid-lowering drug strategies in pancreatic diseases.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eInstrumental\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003evariables (IVs\u003c/strong\u003e\u003cstrong\u003e) selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, genome-wide association study (GWAS) data for LDL-C were obtained from the Medical Research Council-Integrative Epidemiology Unit (MRC-IEU) GWAS database (https://gwas.mrcieu.ac.uk/), specifically from the GWAS ID ieu-b-110, which includes data from 440,546 European individuals. Genetic variants targeting \u003cem\u003eHMGCR\u003c/em\u003e, \u003cem\u003ePCSK9\u003c/em\u003e, and \u003cem\u003eNPC1L1\u003c/em\u003e were used as IVs to simulate the effects of lipid-lowering drugs on LDL-C reduction. The selection of IVs was based on their significant genome-wide association with LDL-C (\u003cem\u003eP\u003c/em\u003e \u0026lt; 5E-08) and their location within \u0026plusmn;100 kb of the \u003cem\u003eHMGCR\u003c/em\u003e/\u003cem\u003ePCSK9\u003c/em\u003e/\u003cem\u003eNPC1L1\u0026nbsp;\u003c/em\u003eloci (Figure 1). To mitigate the impact of substantial linkage disequilibrium (LD) on\u0026nbsp;the\u0026nbsp;results, an LD threshold (r\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e\u0026lt; 0.3) was set. SNPs with an F statistic greater than 30 indicated a strong association between the SNP and the exposure; therefore, SNPs with an F statistic greater than 30 were retained. The F statistic was calculated via the formula F = Beta^2/SE^2. MR analysis requires that SNPs are not directly related to the outcome and are not influenced by confounding factors outside of the exposure of interest. Given that our study investigated three related drug targets, a Bonferroni-corrected \u003cem\u003eP\u003c/em\u003e value threshold of less than 0.017 (0.05/3) was used to identify significant evidence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome Data Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe utilized data on AP, CP, alcoholic acute pancreatitis (AAP), alcoholic chronic pancreatitis (ACP), benign/malignant pancreatic tumors and pancreatic cysts as outcomes for MR analysis, with coronary heart disease (CHD) serving as a positive control. The outcome data, except for those for pancreatic cysts, are available from the MRC-IEU GWAS database (https://gwas.mrcieu.ac.uk/). Data for pancreatic cysts were sourced from the GWAS catalog (https://www.ebi.ac.uk/), as detailed in Table 1. There was no overlap between the exposure cohort (UK Biobank) and the outcome cohort.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 1. Detailed Information on\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ethe\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Studies and Consortia\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;used\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTrait\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDataset\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eResource\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePMID/IOD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAncestor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eYear\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSample Size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eLDL cholesterol\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eieu-b-110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eUK BioBank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32203549\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;Males and Females\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e440546\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCoronary heart disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eieu-a-7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCARDIoGRAMplusC4D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26343387\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMixed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMales and Females\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e184305\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAcute pancreatitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eebi-a-GCST90018789\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;EBI GWAS Catalog\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34594039\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e479902\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eChronic pancreatitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eebi-a-GCST90018821\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;EBI GWAS Catalog\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34594039\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e477528\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAlcohol-induced chronic pancreatitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003efinn-b-ALCOPANCCHRON\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eFinnGen consortium\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eFinnGen consortium (https://www.finngen.fi/fi)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMales and Females\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e218792\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAcohol-induced acute pancreatitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003efinn-b-ALCOPANCACU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eFinnGen consortium\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eFinnGen consortium (https://www.finngen.fi/fi)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;Males and Females\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e218792\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePancreatic pseudocyst\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eebi-a-GCST90044206\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEBI GWAS Catalog\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34737426\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e456348\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePancreatic Malignant Tumour\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eebi-a-GCST90018893\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEBI GWAS Catalog\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34594039\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e476245\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePancreatic Benign Tumour\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003efinn-b-CD2_BENIGN_PANCREAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eFinnGen consortium\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eFinnGen consortium (https://www.finngen.fi/fi)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEuropean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMales and Females\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e218792\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eanalysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSummary data-based Mendelian\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003erandomization\u003c/strong\u003e (\u003cstrong\u003eSMR) and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003esensitivity analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo further evaluate the relationship between lipid-lowering drug targets and pancreatic diseases, we applied the SMR method to the significant positive results, utilizing eQTLs and summary data from\u0026nbsp;GWAS. The magnitude of heterogeneity in the findings was tested via the heterogeneity in dependent instruments (HEIDI) tool (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01 indicated pleiotropy, suggesting that the observed associations might be due to LD).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMR and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003esensitivity analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the inverse-variance weighted (IVW) MR analysis, we focused on genetic variants related to LDL-C levels as IVs. SNPs with an F statistic greater than 30 were included to ensure robust instrument-exposure correlation. To confirm that the selected drug targets did not influence pancreatic disease outcomes through other risk factors, we employed various analytical methods, including IVW, weighted median, and MR Egger. The fixed-effects model of IVW was primarily used for assessment, as it provides reliable causal estimates even in the presence of heterogeneity.\u003c/p\u003e\n\u003cp\u003eTo assess heterogeneity and pleiotropy comprehensively and ensure the robustness of the findings, particularly given that outcomes are not influenced by other risk factors associated with exposure, we used Cochran\u0026apos;s Q statistic and MR‒Egger regression (intercept). When significant heterogeneity (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05) was detected, a multiplicative random effects IVW method was adopted. In the case of observed pleiotropy (intercept \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05), MR‒Egger regression was used as the primary analysis method. The positive control analysis for CHD was performed via the same methods as previously described.\u003c/p\u003e\n\u003cp\u003eSMR analysis was conducted via software version 1.03 (for details, see https://cnsgenomics.com/software/smr/#Overview). Additionally, two-sample data analysis was performed via R version 4.4.0 with the TwoSampleMR package (0.61).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eAssociation of HMGCR with Pancreatic\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eDiseases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the IVW MR analysis, we utilized 19 IVs related to the \u003cem\u003eHMGCR\u003c/em\u003e target. The analysis revealed a significant association between the \u003cem\u003eHMGCR\u003c/em\u003e genetic variant and an increased risk of CP (OR, 2.05; 95% CI: 1.07\u0026ndash;3.91; \u003cem\u003eP\u003c/em\u003e = 0.0298). Additionally, simulated genetic variations in \u003cem\u003eHMGCR\u003c/em\u003e were significantly associated with an increased risk of pancreatic cysts (OR, 7.56; 95% CI: 1.55\u0026ndash;36.82; \u003cem\u003eP\u003c/em\u003e = 0.0123), with the Bonferroni-corrected \u003cem\u003eP\u003c/em\u003e values remaining significant (Figure2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssociation of PCSK9 with Pancreatic\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eDiseases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the \u003cem\u003ePCSK9\u003c/em\u003e target, 33 IVs were analyzed. The IVW MR analysis indicated a significant association between the \u003cem\u003ePCSK9\u003c/em\u003e genetic variant and a decreased risk of ACP (OR, 0.56; 95% CI: 0.34\u0026ndash;0.92; \u003cem\u003eP\u003c/em\u003e = 0.023) (Figure 3). This protective effect suggests potential benefits of PCSK9 inhibition in reducing the risk of CP associated with alcohol consumption. However, significant pleiotropy was observed in the MR analysis of PCSK9 with AP (\u003cem\u003eP\u003c/em\u003e = 0.003), ACP (\u003cem\u003eP\u003c/em\u003e = 0.04), and AAP (\u003cem\u003eP\u003c/em\u003e = 0.00059), indicating that some associations might be influenced by factors other than direct genetic effects on LDL-C levels (Figure 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssociation of NPC1L1 with Pancreatic\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eDiseases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe analysis included 6 IVs related to the \u003cem\u003eNPC1L1\u003c/em\u003e target. The IVW MR analysis demonstrated a significant association between NPC1L1 inhibition and an increased risk of pancreatic cysts (OR, 7.56; 95% CI: 1.55--36.82; \u003cem\u003eP\u003c/em\u003e = 0.0123), with the Bonferroni-corrected \u003cem\u003eP\u003c/em\u003e values remaining significant. NPC1L1 drug targets were associated with a reduced risk of benign pancreatic tumors (OR, 0.01; 95% CI: 0.00--0.84; \u003cem\u003eP\u003c/em\u003e = 0.0415) (Figure 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity Analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure the robustness of our findings, we conducted sensitivity analyses via MR‒Egger regression and Cochran\u0026apos;s Q statistic. The MR‒Egger intercept tests did indicate pleiotropy for the PCSK9 target. However, MR-PRESSO did not detect any outliers, and the results of the MR‒Egger analysis were consistent with those obtained via the weighted median method and the standard IVW method. This consistency across different analytical methods reinforces the reliability of the causal estimates for PCSK9, despite the observed pleiotropy. For HMGCR and NPC1L1, the MR‒Egger intercept tests did not indicate significant pleiotropy, and Cochran\u0026apos;s Q test revealed no evidence of heterogeneity for the outcomes (all \u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05), further supporting the validity of these findings (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"19\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable2 Association between lipid-lowering drugs and pancreatic diseases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eExposure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003enSNP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eMR Egger\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeighted median\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eIVW\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeterogeneity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003ePleiotropy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e95%CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e95%CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e95%CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCochrane\u0026rsquo;s Q\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eQ_\u003cem\u003epval\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003csub\u003eMRPRESSO\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eEgger_Intercept\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003csub\u003ePleiotropy\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003csub\u003eSMR\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003csub\u003eHEIDI\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"8\"\u003e\n \u003cp\u003eHMGCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCoronary heart disease\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.07-3.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.27-2.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.239E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.36-1.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.294E-08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.7175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.542602\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.00805\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAcute pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.71-8.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.83-2.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.97-2.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eChronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.11-8.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.80-4.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.07-3.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.036\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAcohol-induced acute pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.02-29.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.08-1.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.12-1.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAlcohol-induced chronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.07-17.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.58-5.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.59-3.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00938\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBenign neoplasm: Pancreas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00-26.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.03-4.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.04-2.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.079\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePancreatic Malignant Tumour\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.08-5.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.26-1.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.29-1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.063\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.0081\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCyst and Pseudocyst of Pancreas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.04-1076\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.08-79.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.55-36.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0123\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.009004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.048\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.109\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"8\"\u003e\n \u003cp\u003ePCSK9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCoronary heart disease\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.55-2.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.463E-05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.69-2.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.477E-10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.95-2.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.204E-24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.004765\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAcute pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.49-1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.071\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.54-1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.83-1.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.029612\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.003158\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eChronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.49-1.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.47-1.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7-1.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.942\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAcohol-induced acute pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.19-1.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.30-1.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.68-3.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e41.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.107135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.000592\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAlcohol-induced chronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.19-0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0032\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.24-0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0094\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.34-0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.283\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0413\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBenign neoplasm: Pancreas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.22-4.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.993\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.30-4.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.69-6.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePancreatic Malignant Tumour\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.47-1.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.52-1.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.79-1.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.918\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.273\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCyst and Pseudocyst of Pancreas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.16-5.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.30-8.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.53-5.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.987\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0378\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.363\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.660\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.628\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"8\"\u003e\n \u003cp\u003eNPC1L1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCoronary heart disease\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.26-4.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.17-3.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.41-3.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00049\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.018786\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.325\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAcute pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.01-8.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.12-1.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.18-1.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.167\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.009852\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eChronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0..37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00-48.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.05-1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.09-1.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.243\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.002118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAcohol-induced acute pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00-5171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00-1.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0982\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.01-1.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0643\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.06527\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAlcohol-induced chronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.01-33832\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.09-7.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.09-9.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.934\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.0745\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBenign neoplasm: Pancreas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00-870064\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00-2.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.096\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00-0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0415\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.892\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.10594\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePancreatic Malignant Tumour\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00-114.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.08-6.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.774\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.13-4.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.014474\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCyst and Pseudocyst of Pancreas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00-463635175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0-0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00-0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.00071\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.545072\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.18439\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0493\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.813\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSMR Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSMR analysis via summary data revealed significant associations between NPC1L1 inhibition (\u003cem\u003eP\u003c/em\u003e = 0.0493, HEIDI = 0.812842) and HMGCR inhibition (\u003cem\u003eP\u003c/em\u003e = 0.047, HEIDI = 0.108) and the risk of pancreatic cysts. The HEIDI tests suggested no pleiotropy, indicating that the associations were likely direct effects of the genetic variants on pancreatic cyst risk. These results support the findings from the IVW MR analysis and highlight the potential for NPC1L1 and HMGCR inhibitors to influence pancreatic cyst formation.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, MR analysis was applied to investigate the causal relationships of genetic variants in three common lipid-lowering drug targets (HMGCR, PCSK9 and NPC1L1) with several major pancreatic diseases. Our preliminary MR analysis provided credible evidence to support the potential protective effects of statins on CP and pancreatic cysts, the relationship between PCSK9 inhibition and a high risk of ACP and the positive correlation between the genetically proxied inhibition of NPC1L1 and high risks of pancreatic cysts and other benign pancreatic tumors, enriching the current literature and providing new insights into the safety and clinical decisions of these lipid-lowering drugs.\u003c/p\u003e \u003cp\u003eWe first found a causal association between \u003cem\u003eHMGCR\u003c/em\u003e genetic variants and CP, with no heterogeneity or pleiotropic effects, indicating that this study provides strong evidence for the causal effect of statin use on CP. Our observations seem to be consistent with those of previous \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e experiments. Statins have been demonstrated to have pleiotropic effects, such as anti-inflammatory, antifibrotic and antioxidative effects[\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], suggesting the potential ability to treat CP. To confirm this possibility, Wei L \u003cem\u003eet al.\u003c/em\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] used a mouse model and successfully demonstrated that statin treatment delayed the progression of CP. Furthermore, lovastatin was found to successfully inhibit the activation of pancreatic stellate cells, which may prevent fibrosis and the inflammatory response in CP[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Interestingly, a multicenter three-blind randomized controlled trial confirmed that simvastatin prevented RAP, an intermediate stage in the pathogenesis of CP[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Nonetheless, the directly causal relationship of statin use with decreased CP risk in the population remains unclear. The latest evidence suggests that statins can inhibit chronic inflammation by blocking the TBK1-IRF3-IL-33 signaling axis, effectively reducing CP risk in mice and humans[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. These finding and our MR results are highly important, as they suggest that statins may turn to be a safe, effective, and easily available treatment strategy for the prevention of CP.\u003c/p\u003e \u003cp\u003eIn addition, our results revealed that the predicted \u003cem\u003ePCSK9\u003c/em\u003e variant was associated with a reduced risk of ACP, although there was no causal association with CP overall. These findings are striking and explainable. To the best of our knowledge, alcohol abuse is a predominant cause of CP worldwide, especially in Western countries[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Interestingly, the incidence of CP resulting from different etiologies varies across different populations, and the related disease complications of CP also vary. For example, ACP is associated mainly with local inflammatory complications, such as increased risks of pseudocysts and pseudoaneurysms, whereas smoking is associated mainly with fibrotic complications (pancreatic duct lesions, biliary stenosis, etc.) and is negatively associated with inflammation[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Interestingly, Lebeau, Paul F \u003cem\u003eet al.\u003c/em\u003e have demonstrated that PCSK9 deficiency can promote inflammation[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], which seems to explain our findings revealing a causal association of genetically proxied \u003cem\u003ePCSK9\u003c/em\u003e inhibition with elevated risk of ACP. Nonetheless, the role of PCSK9 in the development of general CP is unknown, and, in contrast to what we discussed earlier, the effects of PCSK9 inhibition on inflammatory and fibrotic responses are actually inconsistent in different backgrounds[\u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Given this, our results may provide a better explanation for the causal relationship between genetically proxied \u003cem\u003ePCSK9\u003c/em\u003e inhibition and a high risk of ACP from a genetic perspective, indicating that PCSK9 inhibitors should be used carefully when prescribing lipid-lowering drugs in chronic alcoholism patients. However, our findings have suggested that there is no significant causal relationship between PCSK9 and CP risk. To note, we simulated the \u003cem\u003ePCSK9\u003c/em\u003e variant by genetic instrumentals to predict its relationship with pancreatitis, which is an original effect. In other words, there are different causal relationships between genetically proxied \u003cem\u003ePCSK9\u003c/em\u003e inhibition and various pancreatitis, which may attribute to different genetic milieu in different diseases, while the causal relationships in real world may be long-term and more complex.\u003c/p\u003e \u003cp\u003eInterestingly, our results suggest that genetic variants in \u003cem\u003eHMGCR\u003c/em\u003e are associated with a high risk of pancreatic cysts while \u003cem\u003eNPC1L1\u003c/em\u003e genetic variants are negatively related to them, which are important to the implications for the clinical management of pancreatic cysts. To our best knowledge, there was no direct evidence to show any causal association between commonly-used medications and the risks of pancreatic cysts, our results are the first to indicate the causal relationships of lipid-lowering medications with pancreatic cysts.. Postpancreatitis pseudocyst is mostly common in histological classification of pancreatic pseudocyst, characterized as an inflammatory cyst preserving abnormal fluid in or around the pancreas[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Conversely, pseudocyst is also one of the most common sequela of pancreatitis. A recent cohort study demonstrated the association between statin usage and a reduced risk of PPDM, indicating that statins may have potentially protective effects on chronic complications of AP or CP[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Additionally, the anti-fibrotic and anti-inflammatory effects of statins may have inhibitory effects on cyst formation[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. On the other hand, PCNs, including IPMNs and MCNs, are considered malignant precursors of PC[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], while few previous studies have focused on the correlation of statins with PCNs. Notably, a recent multi-omics study found that IPMN profiles showed significant lipid pathway alterations[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], suggesting that regulating abnormal lipid profiles may have the potential benefits. In addition, the mutations of TP53 and the Kirsten rat sarcoma viral oncogene homolog (KRAS) are the most important mutations associated with neoplastic cysts[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], while statins have been demonstrated to induce the degradation of mutant TP53 and KRAS by inhibiting the mevalonate pathway[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], suggesting a potential association of statins with PCNs. These findings provide indirect support for statins\u0026rsquo; potential protective role in pancreatic cysts. Aligned well with these findings, the findings from our results are the first to demonstrate an association between an easily available and inexpensive strategy, statins, and a reduced risk of pancreatic cysts, though it requires further experiments and clinical studies to confirm it.\u003c/p\u003e \u003cp\u003eCurrently, surgical strategies are mainly adopted for the treatment of pancreatic cysts, while the pharmacological and toxicological effects of drugs on pancreatic cysts are an important but still unsolved problem. Converse to statins, we find that NPC1L1 inhibitors may increase the risk of pancreatic cysts and benign pancreatic tumors, which is a mysterious area that has not yet been reported. This can generate hypotheses for future studies and provide a possible pharmacological treatment strategy for clinicians. Our results seem to give some hints that clinicians should pay more attention to the use of statins, and take more caution with NPC1L1 inhibitors when developing lipid-regulating drug strategies for patients at high risk of developing pancreatic cysts. More importantly, these findings also inform longitudinal prospective cohort studies to examine the use of these two lipid-lowering drugs and their relationship with pancreatic cysts and advise randomized controlled trials to examine long-term outcomes.\u003c/p\u003e \u003cp\u003eThe causal relationship of lipid-lowering drugs, especially statins, with AP or PC has attracted much attention, and inconsistent results have been obtained in different observational studies. Whether in AP or PC, the causal associations of statins and each one of the two diseases ranged from elevated[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e] or decreased[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] risk to no significant association[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan additionalcitationids=\"CR51\" citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. However, it is difficult to confidently obtain causal relationships from observational or other traditional epidemiological studies owing to the potential residual impact of incompletely measured confounding or bias. To the best of our knowledge, this study is the first to employ drug target MR analysis to provide new insights into the causal relationships between lipid-lowering drugs and AP and PC, enriching the current literature. Although we did not find a causal relationship between the three lipid-lowering drug target genetic instruments and AP or PC, our MR analysis, by genetic verification, eliminated confounders and bias as much as possible. Nonetheless, other underlying associations are unclear and require further investigation.\u003c/p\u003e \u003cp\u003eThere are several limitations to our research. First, as with all MR studies, IV assumptions are not empirically verifiable. It is unable to completely eliminate the possibility of confounding bias and/or horizontal pleiotropy, although we performed multiple sensitivity analyses to scrutinize the research hypotheses of MR. Second, it is worth noting that the eQTLs and GWAS data used in this study were from European populations, where cholelithiasis and alcohol are the main causes of AP and CP, whereas in China, hyperlipidemic acute pancreatitis has become non-negligible. Therefore, validation of the generality of our results in broader population cohorts is needed, including conducting similar MR analyses in different population cohorts and exploring potential genetic and environmental interactions.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOn the basis of our MR analysis, the genetically proxied inhibition of \u003cem\u003eHMGCR\u003c/em\u003e was associated with an increased risk of CP and pancreatic cysts, the genetically proxied inhibition of \u003cem\u003ePCSK9\u003c/em\u003e was associated with a decreased risk of alcohol-related CP, and the \u003cem\u003eNPC1L1\u003c/em\u003e genetically proxied inhibition were associated with decreased risks of benign pancreatic tumors and pancreatic cysts. Our findings strongly support the use of statins as a strategy to prevent the occurrence and development of CP. Moreover, our results provide advice to clinicians on clinical decision-making -- statins should be used rather than NPC1L1 inhibitors as possible when people at high risk of pancreatic cysts need lipid-lowering strategies, thereby achieving more personalized therapy. In addition, the findings indicate that the genetic variants of the three lipid-lowering drugs are not significantly causally related to AP or PC, further genetically verifying their safety for these pancreatic diseases.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eAcute pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eChronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003ePancreatic cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRAP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eRecurrent\u0026nbsp;acute pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLDL-C\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eLow density lipoprotein-cholesterol\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLDLR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eLow density lipoprotein receptor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHMGCR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003e3-hydroxy-3-methylglutaryl-CoA reductase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNPC1L1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eNiemann-Pick C1-Like 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePCSK9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eProprotein convertase subtilisin/keexin type 9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePCNs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003ePancreatic cystic neoplasms\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMCNs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eMucinous cystic neoplasms\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIPMNs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eIntraductal papillary mucinous neoplasms\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePPDM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003ePost pancreatitis diabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eMendelian randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSNPs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eSingle-nucleotide polymorphisms\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGWAS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eGenome-wide association study\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMRC-IEU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eMedical Research Council-Integrative Epidemiology Unit\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIVs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eInstrumental variables\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eLinkage disequilibrium\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHEIDI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eHeterogeneity in dependent instruments\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eAlcoholic acute pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eACP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eAlcoholic chronic pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCHD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eCoronary heart disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eSummary data-based Mendelian Randomization\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIVW\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eInverse-variance weighted\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKRAS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eKirsten rat sarcoma viral oncogene homolog\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e\u003cstrong\u003ecknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge the participants and investigators of the UK Biobank and FinnGen studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYong-Chuan Chen and Can-E Tang designed the study; Ge Yang conducted the data analysis; Ge Yang and Yi-Zhuo Feng prepared all the figures and tables; Yi-Zhuo Feng and Ge Yang edited the manuscript. Yan-Jiao Ou, Hong Zhang, Can-E Tang and Yong-Chuan Chen reviewed and revised the manuscript. All the authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Natural Science Foundation of Hunan Province (2024JJ5611) and the National Natural Science Foundation of China (82370642).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe genome-wide association study (GWAS) data for LDL-C used in this study were obtained from the Medical Research Council-Integrative Epidemiology Unit (MRC-IEU) GWAS database under GWAS ID ieu-b-110, accessible at https://gwas.mrcieu.ac.uk/. Data on acute pancreatitis (AP), chronic pancreatitis (CP), alcoholic acute pancreatitis (AAP), alcoholic chronic pancreatitis (ACP), benign/malignant pancreatic tumors, and coronary heart disease (CHD) were also sourced from the MRC-IEU GWAS database, which is accessible at https://gwas.mrcieu.ac.uk/. Data for pancreatic cysts were obtained from the GWAS Catalog, accessible at https://www.ebi.ac.uk/gwas/. All relevant data supporting the findings of this study are included within the article and its supplementary materials. For any additional information or data requests, please contact the corresponding authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll analyses were performed on anonymized summary statistics from published GWAS with appropriate institutional review board approval. Separate institutional review board approval was not required for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are no competing interests. The research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eXiao, A. Y. et al. Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies. \u003cem\u003eLancet Gastroenterol. Hepatol.\u003c/em\u003e \u003cb\u003e1\u003c/b\u003e, 45 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeery, A. F. et al. Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2021. \u003cem\u003eGASTROENTEROLOGY\u003c/em\u003e 162 621 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHines, O. J. \u0026amp; Pandol, S. J. Management of chronic pancreatitis. \u003cem\u003eBMJ\u003c/em\u003e. \u003cb\u003e384\u003c/b\u003e, e70920 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiegel, R. L., Giaquinto, A. N. \u0026amp; Jemal, A. Cancer statistics, 2024. \u003cem\u003eCA Cancer J. Clin.\u003c/em\u003e \u003cb\u003e74\u003c/b\u003e, 12 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. \u003cem\u003eCANCER RES.\u003c/em\u003e \u003cb\u003e74\u003c/b\u003e, 2913 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark, W., Chawla, A. \u0026amp; O'Reilly, E. M. Pancreatic Cancer: A Review. \u003cem\u003eJAMA\u003c/em\u003e 326 851 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGardner, T. B., Park, W. G. \u0026amp; Allen, P. J. Diagnosis and Management of Pancreatic Cysts. \u003cem\u003eGASTROENTEROLOGY\u003c/em\u003e 167 454 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang, A. L. \u0026amp; McNabb-Baltar, J. Hypertriglyceridemia and acute pancreatitis. \u003cem\u003ePANCREATOLOGY\u003c/em\u003e. \u003cb\u003e20\u003c/b\u003e, 795 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHong, W. et al. Relationship between low-density lipoprotein cholesterol and severe acute pancreatitis (the lipid paradox). \u003cem\u003eTHER. CLIN. RISK MANAG\u003c/em\u003e. \u003cb\u003e14\u003c/b\u003e, 981 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTruninger, K., Schmid, P. A., Hoffmann, M. M., Bertschinger, P. \u0026amp; Ammann, R. W. Recurrent acute and chronic pancreatitis in two brothers with familial chylomicronemia syndrome. \u003cem\u003ePANCREAS\u003c/em\u003e 32 215 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYin, X. et al. Lipid metabolism in pancreatic cancer: emerging roles and potential targets. \u003cem\u003eCancer Commun. (Lond)\u003c/em\u003e. \u003cb\u003e42\u003c/b\u003e, 1234 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRevilla, G. et al. HDL and endocrine-related cancer: From pathogenic mechanisms to therapies. \u003cem\u003eSEMIN CANCER BIOL.\u003c/em\u003e \u003cb\u003e73\u003c/b\u003e, 134 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePirillo, A., Catapano, A. L. \u0026amp; Norata, G. D. Niemann-Pick C1-Like 1 (NPC1L1) Inhibition and Cardiovascular Diseases. \u003cem\u003eCURR. MED. CHEM.\u003c/em\u003e \u003cb\u003e23\u003c/b\u003e, 983 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStein, E. A. \u0026amp; Raal, F. J. Lipid-Lowering Drug Therapy for CVD Prevention: Looking into the Future. \u003cem\u003eCURR. CARDIOL. REP.\u003c/em\u003e \u003cb\u003e17\u003c/b\u003e, 104 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDadu, R. T. \u0026amp; Ballantyne, C. M. Lipid lowering with PCSK9 inhibitors. \u003cem\u003eNAT. REV. CARDIOL.\u003c/em\u003e \u003cb\u003e11\u003c/b\u003e, 563 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKavalipati, N., Shah, J., Ramakrishan, A. \u0026amp; Vasnawala, H. Pleiotropic effects of statins. \u003cem\u003eIndian J. Endocrinol. Metab.\u003c/em\u003e \u003cb\u003e19\u003c/b\u003e, 554 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBadalov, N. et al. Drug-induced acute pancreatitis: an evidence-based review. \u003cem\u003eClin. Gastroenterol. Hepatol.\u003c/em\u003e \u003cb\u003e5 648\u003c/b\u003e, 644 (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePreiss, D. et al. Lipid-modifying therapies and risk of pancreatitis: a meta-analysis. \u003cem\u003eJAMA\u003c/em\u003e. \u003cb\u003e308\u003c/b\u003e, 804 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTalukdar, R. \u0026amp; Vege, S. S. Acute pancreatitis. \u003cem\u003eCurr. Opin. Gastroenterol.\u003c/em\u003e \u003cb\u003e31\u003c/b\u003e, 374 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu, B. U., Pandol, S. J. \u0026amp; Liu, I. L. Simvastatin is associated with reduced risk of acute pancreatitis: findings from a regional integrated healthcare system. \u003cem\u003eGUT\u003c/em\u003e. \u003cb\u003e64\u003c/b\u003e, 133 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCardenas-Jaen, K. et al. Simvastatin in the Prevention of Recurrent Pancreatitis: Design and Rationale of a Multicenter Triple-Blind Randomized Controlled Trial, the SIMBA Trial. \u003cem\u003eFront. Med. (Lausanne)\u003c/em\u003e. \u003cb\u003e7\u003c/b\u003e, 494 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWei, L., Yamamoto, M., Harada, M. \u0026amp; Otsuki, M. Treatment with pravastatin attenuates progression of chronic pancreatitis in rat. \u003cem\u003eLAB. INVEST.\u003c/em\u003e \u003cb\u003e91\u003c/b\u003e, 872 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBagheri, H., Adeli, O. A., Heidari-Soureshjani, S., Azadegan-Dehkordi, Z. \u0026amp; Mt, S. C. The Relationship between Statin Intake and Risk of Pancreatic Cancer: A Systematic Review and Meta-Analysis. \u003cem\u003eCurr. Drug Res. Rev.\u003c/em\u003e (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaito, K. et al. Exposure and Pancreatic Cancer Incidence: A Japanese Regional Population-Based Cohort Study, the Shizuoka Study. \u003cem\u003eCancer Prev. Res. (Phila)\u003c/em\u003e. \u003cb\u003e14\u003c/b\u003e, 863 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKirkegard, J., Lund, J. L., Mortensen, F. V. \u0026amp; Cronin-Fenton, D. Statins and pancreatic cancer risk in patients with chronic pancreatitis: A Danish nationwide population-based cohort study. \u003cem\u003eINT. J. CANCER\u003c/em\u003e. \u003cb\u003e146\u003c/b\u003e, 610 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBang, U. C., Watanabe, T. \u0026amp; Bendtsen, F. The relationship between the use of statins and mortality, severity, and pancreatic cancer in Danish patients with chronic pancreatitis. \u003cem\u003eEur. J. Gastroenterol. Hepatol.\u003c/em\u003e \u003cb\u003e30\u003c/b\u003e, 346 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHamada, T. et al. Statin use and pancreatic cancer risk in two prospective cohort studies. \u003cem\u003eJ. GASTROENTEROL.\u003c/em\u003e \u003cb\u003e53\u003c/b\u003e, 959 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSahani, D. V. et al. Cystic pancreatic lesions: classification and management. \u003cem\u003eJ. AM. COLL. RADIOL.\u003c/em\u003e \u003cb\u003e6\u003c/b\u003e, 376 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThiruvengadam, N. R. et al. Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis. \u003cem\u003eClin. Gastroenterol. Hepatol.\u003c/em\u003e \u003cb\u003e21\u003c/b\u003e, 1214 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavey, S. G. \u0026amp; Hemani, G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. \u003cem\u003eHUM. MOL. GENET.\u003c/em\u003e \u003cb\u003e23\u003c/b\u003e, R89 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGill, D. et al. Mendelian randomization for studying the effects of perturbing drug targets. \u003cem\u003eWellcome Open. Res.\u003c/em\u003e \u003cb\u003e6\u003c/b\u003e, 16 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSolheim, S., Seljeflot, I., Arnesen, H., Eritsland, J. \u0026amp; Eikvar, L. Reduced levels of TNF alpha in hypercholesterolemic individuals after treatment with pravastatin for 8 weeks. \u003cem\u003eATHEROSCLEROSIS\u003c/em\u003e. \u003cb\u003e157\u003c/b\u003e, 411 (2001).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, C. et al. Pravastatin treatment attenuates interstitial inflammation and fibrosis in a rat model of chronic cyclosporine-induced nephropathy. \u003cem\u003eAm. J. Physiol. Ren. Physiol.\u003c/em\u003e \u003cb\u003e286\u003c/b\u003e, F46 (2004).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoriyama, T. et al. Fluvastatin suppresses oxidative stress and fibrosis in the interstitium of mouse kidneys with unilateral ureteral obstruction. \u003cem\u003eKIDNEY INT\u003c/em\u003e 59 (2001). (2095).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJaster, R., Brock, P., Sparmann, G., Emmrich, J. \u0026amp; Liebe, S. Inhibition of pancreatic stellate cell activation by the hydroxymethylglutaryl coenzyme A reductase inhibitor lovastatin. \u003cem\u003eBIOCHEM. PHARMACOL.\u003c/em\u003e \u003cb\u003e65\u003c/b\u003e, 1295 (2003).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMachicado, J. D. \u0026amp; Yadav, D. Epidemiology of Recurrent Acute and Chronic Pancreatitis: Similarities and Differences. \u003cem\u003eDig. Dis. Sci.\u003c/em\u003e \u003cb\u003e62\u003c/b\u003e, 1683 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark, J. H. et al. Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression. \u003cem\u003eNAT. COMMUN.\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e, 4099 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBang, U. C., Benfield, T., Hyldstrup, L., Bendtsen, F. \u0026amp; Beck, J. J. Mortality, cancer, and comorbidities associated with chronic pancreatitis: a Danish nationwide matched-cohort study. \u003cem\u003eGASTROENTEROLOGY\u003c/em\u003e. \u003cb\u003e146\u003c/b\u003e, 989 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgarwal, S. et al. Natural course of chronic pancreatitis and predictors of its progression. \u003cem\u003ePANCREATOLOGY\u003c/em\u003e. \u003cb\u003e20\u003c/b\u003e, 347 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLebeau, P. F. et al. Pcsk9 knockout exacerbates diet-induced non-alcoholic steatohepatitis, fibrosis and liver injury in mice. \u003cem\u003eJHEP Rep.\u003c/em\u003e \u003cb\u003e1\u003c/b\u003e, 418 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD'Onofrio, N. et al. SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells. \u003cem\u003eTHERANOSTICS\u003c/em\u003e. \u003cb\u003e13\u003c/b\u003e, 531 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDong, X. C. Sirtuin 6-A Key Regulator of Hepatic Lipid Metabolism and Liver Health. \u003cem\u003eCELLS-BASEL\u003c/em\u003e 12 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIoannou, G. N. et al. Pcsk9 Deletion Promotes Murine Nonalcoholic Steatohepatitis and Hepatic Carcinogenesis: Role of Cholesterol. \u003cem\u003eHepatol. Commun.\u003c/em\u003e \u003cb\u003e6\u003c/b\u003e, 780 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Jong, K. et al. High prevalence of pancreatic cysts detected by screening magnetic resonance imaging examinations. \u003cem\u003eClin. Gastroenterol. Hepatol.\u003c/em\u003e \u003cb\u003e8\u003c/b\u003e, 806 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGaiser, R. A. et al. Integrated targeted metabolomic and lipidomic analysis: A novel approach to classifying early cystic precursors to invasive pancreatic cancer. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cb\u003e9\u003c/b\u003e, 10208 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen, J. C., Beal, E. W., Pawlik, T. M., Cloyd, J. \u0026amp; Dillhoff, M. E. Molecular Diagnosis of Cystic Neoplasms of the Pancreas: a Review. \u003cem\u003eJ. GASTROINTEST. SURG.\u003c/em\u003e \u003cb\u003e24\u003c/b\u003e, 1201 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu, D. et al. Inhibition of mutant Kras and p53-driven pancreatic carcinogenesis by atorvastatin: Mainly via targeting of the farnesylated DNAJA1 in chaperoning mutant p53. \u003cem\u003eMol Carcinog\u003c/em\u003e 58 (2019). (2052).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Connor, C. E., Dang, B. Q., Miles, B. \u0026amp; Mackey, J. Statin Therapy and Pancreatitis: A Multi-Institutional Retrospective Analysis. \u003cem\u003eCureus\u003c/em\u003e. \u003cb\u003e16\u003c/b\u003e, e51723 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin, C. M., Liao, K. F., Lin, C. L. \u0026amp; Lai, S. W. Use of Simvastatin and Risk of Acute Pancreatitis: A Nationwide Case-Control Study in Taiwan. \u003cem\u003eJ. CLIN. PHARMACOL.\u003c/em\u003e \u003cb\u003e57\u003c/b\u003e, 918 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePoropat, G. et al. Statin use is not associated with an increased risk of acute pancreatitis-A meta-analysis of observational studies. \u003cem\u003eUnited Eur. Gastroenterol. J.\u003c/em\u003e \u003cb\u003e6\u003c/b\u003e, 1206 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBa, D. M., Zhang, Y., Chinchilli, V. M. \u0026amp; Maranki, J. Statins exposure and acute pancreatitis: a retrospective cohort study using a large national insurance database. \u003cem\u003eBMJ OPEN\u003c/em\u003e 13 e77591 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimon, M. S. et al. Prospective analysis of association between statins and pancreatic cancer risk in the Women's Health Initiative. \u003cem\u003eCancer Causes Control\u003c/em\u003e. \u003cb\u003e27\u003c/b\u003e, 415 (2016).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pancreatic diseases, Hypocholesterolemic drugs, Statins, Mendelian randomization","lastPublishedDoi":"10.21203/rs.3.rs-5331443/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5331443/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePancreatic diseases, usually including various pancreatitis, pancreatic cancer and pancreatic cysts, present great challenges to the global health care system. Abnormal lipid profiles are common in these pancreatic diseases, suggesting the lipid-lowering medications may have potential effects on them. However, given the current evidence, the effects of lipid-lowering drugs on pancreatic diseases are inconsistent. Therefore, this study employs drug-targeted Mendelian randomization to investigate the causal relationships between hypocholesterolemic drugs (statins, ezetimibe and PCSK9 inhibitors) and various pancreatic diseases. The findings of our results indicate significant associations between the genetically proxied inhibition of HMGCR and decreased risks of chronic pancreatitis and pancreatic cysts, while PCSK9 inhibition is associated with an increased risk of alcoholic chronic pancreatitis. In addition, NPC1L1 inhibition is linked to an increased risk of pancreatic cysts and benign pancreatic tumors. These results provide insights for screening personalized medications for pancreatic diseases, highlighting the potential benefits of statins in pancreatitis and its complication and the need for caution when prescribing specific lipid-lowering drugs to patients predisposed to pancreatic conditions.\u003c/p\u003e","manuscriptTitle":"Impact of Lipid-Lowering Therapy on Pancreatic Health: Insights from Mendelian Randomization","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-17 09:47:53","doi":"10.21203/rs.3.rs-5331443/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e36f085f-87ac-42ea-a1c0-d7397439e39f","owner":[],"postedDate":"December 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":41128345,"name":"Health sciences/Diseases"},{"id":41128346,"name":"Health sciences/Medical research"},{"id":41128347,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-02-28T14:23:54+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-17 09:47:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5331443","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5331443","identity":"rs-5331443","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}